A complex network of regulatory controls governs the patterns of gene expression. Enabled by the tools of molecular cloning, initial experimental queries into the gene regulatory network elucidated a wide array of transcription factors and their cognate binding sites from hundreds of genes. The recent fusion of genome-scale experimental tools, a more comprehensive gene catalog, and concomitant advances in computational methodology, has extended the range of questions being posed. The potential to further our understanding of the biochemical mechanisms of transcriptional regulation and to accelerate the delineation of regulatory control regions in the human genome is enormous.